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1
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Raoufi A, Soleimani Samarkhazan H, Nouri S, Khaksari MN, Abbasi Sourki P, Sargazi Aval O, Baradaran B, Aghaei M. Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets. Clin Exp Med 2025; 25:73. [PMID: 40048037 PMCID: PMC11885342 DOI: 10.1007/s10238-025-01588-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025]
Abstract
Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.
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Affiliation(s)
- Atieh Raoufi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan University of Medical Science, Zanjan, Iran
| | - Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Nouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Navid Khaksari
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Abbasi Sourki
- Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Omolbanin Sargazi Aval
- Department of Hematology, Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran.
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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2
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Zeka F, Angori S, Rutishauser D, Moch H, Posovszky C, Amin K, Holtan S, Güngör T, Drozdov D. High Amphiregulin Expression in Intestinal Biopsies of Pediatric Patients with Severe Acute Graft-Versus-Host Disease. Transplant Cell Ther 2025:S2666-6367(25)01054-1. [PMID: 40015568 DOI: 10.1016/j.jtct.2025.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 02/16/2025] [Accepted: 02/21/2025] [Indexed: 03/01/2025]
Abstract
Acute graft-versus-host disease (GvHD) is a major complication of hematopoietic cell transplantation (HCT). Despite of recent advances in prophylaxis, diagnosis and treatment it is still a serious cause of morbidity and mortality after HCT. Amphiregulin (AREG) is an epidermal growth factor receptor ligand known for restoring damaged intestinal tissue. AREG has been studied as a blood biomarker in acute GvHD and was found predictive of steroid response and mortality. However, the expression of AREG in intestinal tissue in pediatric patients with acute GvHD is unknown. The aim of this study is to analyze and evaluate AREG expression in intestinal tissue biopsies of pediatric patients with GvHD, in comparison to patients with inflammatory bowel disease (IBD) and a control group with no pathological findings to provide insights in the biological tissue expression of this potential diagnostic and prognostic biomarker. We performed a retrospective study with pediatric patients who had an intestinal biopsy performed after HCT between 2010 and 2021, patients who had a diagnosis of IBD and patients with normal findings at the University Children's Hospital Zurich. Intestinal biopsies were stained for AREG. We used a semi-quantitative score ranging from 0 (not present) to 3 (intense) to grade the AREG expression. The grading was performed by a pathologist blinded to the group allocation. Lerner scores were also performed. The median AREG scores between the groups were compared using multivariable linear regression with age and sex as confounders. The study protocol was approved by the Ethical committee of Canton Zürich, Switzerland, number 2022-01037. Overall, 59 biopsies were stained for AREG, 20 after HCT (6 patients with severe GvHD, 5 with mild GvHD and 9 without GvHD), 19 with IBD and 20 controls. The median for the AREG overall grade for control group was 2, for the HCT with severe GvHD group 2.5 (P = .060) and for the IBD group 2.5 (P = .007). The results for the AREG epithelium and lamina propria grades were similar. There were no differences in survival between patients with GvHD with overall AREG scores below and greater or equal to the median of 2.5. This study showed that AREG scores were higher in intestinal biopsies from patients with severe GvHD and IBD compared to controls and patients with mild or no GvHD. Consequently, AREG staining could potentially be used as an additional marker for severe inflammation as seen in GvHD and IBD.
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Affiliation(s)
- Fjolla Zeka
- Department of Hematology/Oncology/Immunology, Gene-therapy, and Stem Cell Transplantation University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland; Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | - Silvia Angori
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Dorothea Rutishauser
- Department of Pathology and Molecular Pathology, University Hospital Zürich and University of Zürich, Zürich, Switzerland
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zürich and University of Zürich, Zürich, Switzerland
| | - Carsten Posovszky
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, University Children's Hospital Zurich, Zürich, Switzerland
| | - Khalid Amin
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Shernan Holtan
- Division of Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, Minnesota; Transplant and Cellular Therapies, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Tayfun Güngör
- Department of Hematology/Oncology/Immunology, Gene-therapy, and Stem Cell Transplantation University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland
| | - Daniel Drozdov
- Department of Hematology/Oncology/Immunology, Gene-therapy, and Stem Cell Transplantation University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland; Division of Pediatric Hematology and Oncology, Children's Hospital, Kantonsspital Aarau, Aarau, Switzerland.
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3
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Chandra G, Wang J, Siirtola P, Röning J. Leveraging machine learning for predicting acute graft-versus-host disease grades in allogeneic hematopoietic cell transplantation for T-cell prolymphocytic leukaemia. BMC Med Res Methodol 2024; 24:112. [PMID: 38734644 PMCID: PMC11088760 DOI: 10.1186/s12874-024-02237-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024] Open
Abstract
Orphan diseases, exemplified by T-cell prolymphocytic leukemia, present inherent challenges due to limited data availability and complexities in effective care. This study delves into harnessing the potential of machine learning to enhance care strategies for orphan diseases, specifically focusing on allogeneic hematopoietic cell transplantation (allo-HCT) in T-cell prolymphocytic leukemia. The investigation evaluates how varying numbers of variables impact model performance, considering the rarity of the disease. Utilizing data from the Center for International Blood and Marrow Transplant Research, the study scrutinizes outcomes following allo-HCT for T-cell prolymphocytic leukemia. Diverse machine learning models were developed to forecast acute graft-versus-host disease (aGvHD) occurrence and its distinct grades post-allo-HCT. Assessment of model performance relied on balanced accuracy, F1 score, and ROC AUC metrics. The findings highlight the Linear Discriminant Analysis (LDA) classifier achieving the highest testing balanced accuracy of 0.58 in predicting aGvHD. However, challenges arose in its performance during multi-class classification tasks. While affirming the potential of machine learning in enhancing care for orphan diseases, the study underscores the impact of limited data and disease rarity on model performance.
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Affiliation(s)
- Gunjan Chandra
- Biomimetics and Intelligent Systems Group, University of Oulu, Pentti Kaiteran katu 1, 90570, Oulu, Finland.
| | - Junfeng Wang
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Pekka Siirtola
- Biomimetics and Intelligent Systems Group, University of Oulu, Pentti Kaiteran katu 1, 90570, Oulu, Finland
| | - Juha Röning
- Biomimetics and Intelligent Systems Group, University of Oulu, Pentti Kaiteran katu 1, 90570, Oulu, Finland
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4
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Choi SW. Unveiling amphiregulin: a blood-based biomarker for graft- versus-host disease risk assessment and monitoring. Haematologica 2024; 109:1315-1316. [PMID: 37822241 PMCID: PMC11063830 DOI: 10.3324/haematol.2023.284148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 10/05/2023] [Indexed: 10/13/2023] Open
Abstract
Not available.
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Affiliation(s)
- Sung Won Choi
- University of Michigan, Michigan Medicine, Blood and Marrow Transplantation Program; Ann Arbor, MI.
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Holtan SG, El Jurdi N, Rashidi A, Betts BC, Demorest C, Galvin JP, MacMillan ML, Weisdorf DJ, Panoskaltsis-Mortari A, Pratta MA. Amphiregulin as a biomarker for monitoring lifethreatening acute graft- versus-host disease: secondary analysis of two prospective clinical trials. Haematologica 2024; 109:1557-1561. [PMID: 37706330 PMCID: PMC11063869 DOI: 10.3324/haematol.2023.283215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023] Open
Abstract
Not available.
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Affiliation(s)
- Shernan G. Holtan
- University of Minnesota, Adult Blood and Marrow Transplant & Cell Therapy Program, Minneapolis, MN
| | - Najla El Jurdi
- University of Minnesota, Adult Blood and Marrow Transplant & Cell Therapy Program, Minneapolis, MN
| | - Armin Rashidi
- University of Minnesota, Adult Blood and Marrow Transplant & Cell Therapy Program, Minneapolis, MN
- Fred Hutchinson Cancer Center, Seattle, WA
| | - Brian C. Betts
- University of Minnesota, Adult Blood and Marrow Transplant & Cell Therapy Program, Minneapolis, MN
| | - Connor Demorest
- Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | | | - Margaret L. MacMillan
- University of Minnesota, Pediatric Blood and Marrow Transplant & Cell Therapy Program, Minneapolis, MN, USA
| | - Daniel J. Weisdorf
- University of Minnesota, Adult Blood and Marrow Transplant & Cell Therapy Program, Minneapolis, MN
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6
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Arnhold V, Chang WY, Jansen SA, Thangavelu G, Calafiore M, Vinci P, Fu YY, Ito T, Takashima S, Egorova A, Kuttiyara J, Perlstein A, van Hoesel M, Liu C, Blazar BR, Lindemans CA, Hanash AM. Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage. J Clin Invest 2024; 134:e155880. [PMID: 38349762 PMCID: PMC10977993 DOI: 10.1172/jci155880] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/06/2024] [Indexed: 02/23/2024] Open
Abstract
Corticosteroid treatment (CST) failure is associated with poor outcomes for patients with gastrointestinal (GI) graft-versus-host disease (GVHD). CST is intended to target the immune system, but the glucocorticoid receptor (GR) is widely expressed, including within the intestines, where its effects are poorly understood. Here, we report that corticosteroids (CS) directly targeted intestinal epithelium, potentially worsening immune-mediated GI damage. CS administered to mice in vivo and intestinal organoid cultures ex vivo reduced epithelial proliferation. Following irradiation, immediate CST mitigated GI damage but delayed treatment attenuated regeneration and exacerbated damage. In a murine steroid-refractory (SR) GVHD model, CST impaired epithelial regeneration, worsened crypt loss, and reduced intestinal stem cell (ISC) frequencies. CST also exacerbated immune-mediated damage in organoid cultures with SR, GR-deficient T cells or IFN-γ. These findings correlated with CS-dependent changes in apoptosis-related gene expression and STAT3-related epithelial proliferation. Conversely, IL-22 administration enhanced STAT3 activity and overcame CS-mediated attenuation of regeneration, reducing crypt loss and promoting ISC expansion in steroid-treated mice with GVHD. Therefore, CST has the potential to exacerbate GI damage if it fails to control the damage-inducing immune response, but this risk may be countered by strategies augmenting epithelial regeneration, thus providing a rationale for clinical approaches combining such tissue-targeted therapies with immunosuppression.
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Affiliation(s)
- Viktor Arnhold
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Winston Y. Chang
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Medical College, New York, New York, USA
| | - Suze A. Jansen
- Division of Pediatrics, Regenerative Medicine Center, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
- Department of Stem Cell Transplantation, Princess Maximá Center for Pediatric Oncology, Utrecht, Netherlands
| | - Govindarajan Thangavelu
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapy, University of Minnesota, Minneapolis, Minnesota, USA
| | - Marco Calafiore
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Paola Vinci
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ya-Yuan Fu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Takahiro Ito
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Shuichiro Takashima
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Hematology, NHO Kyushu Medical Center, Fukuoka, Fukuoka, Japan
| | - Anastasiya Egorova
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jason Kuttiyara
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Adam Perlstein
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Marliek van Hoesel
- Division of Pediatrics, Regenerative Medicine Center, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
- Department of Stem Cell Transplantation, Princess Maximá Center for Pediatric Oncology, Utrecht, Netherlands
| | - Chen Liu
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapy, University of Minnesota, Minneapolis, Minnesota, USA
| | - Caroline A. Lindemans
- Division of Pediatrics, Regenerative Medicine Center, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
- Department of Stem Cell Transplantation, Princess Maximá Center for Pediatric Oncology, Utrecht, Netherlands
| | - Alan M. Hanash
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Medical College, New York, New York, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, and Department of Medicine, Weill Cornell Medical College, New York, New York, USA
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7
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Koyama M. A potential tissue-based biomarker in gut GVHD. Blood 2023; 142:1768-1769. [PMID: 37995106 DOI: 10.1182/blood.2023022229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2023] Open
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8
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Patel BK, Raabe MJ, Lang ER, Song Y, Lu C, Deshpande V, Nieman LT, Aryee MJ, Chen YB, Ting DT, DeFilipp Z. Spatial transcriptomics reveals distinct tissue niches linked with steroid responsiveness in acute gastrointestinal GVHD. Blood 2023; 142:1831-1844. [PMID: 37699201 PMCID: PMC10731919 DOI: 10.1182/blood.2023020644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/14/2023] [Accepted: 08/14/2023] [Indexed: 09/14/2023] Open
Abstract
Severe acute graft-versus-host disease (aGVHD) is associated with significant mortality and morbidity, especially in steroid-resistant (SR) cases. Spatial transcriptomic technology can elucidate tissue-based interactions in vivo and possibly identify predictors of treatment response. Tissue sections from 32 treatment-naïve patients with biopsy-confirmed lower gastrointestinal (GI) aGVHD were obtained. The GeoMx digital spatial profiler was used to capture transcriptome profiles of >18 000 genes from different foci of immune infiltrates, colonic epithelium, and vascular endothelium. Each tissue compartment sampled showed 2 distinct clusters that were analyzed for differential expression and spatially resolved correlation of gene signatures. Classic cell-mediated immunity signatures, normal differentiated epithelial cells, and inflamed vasculature dominated foci sampled from steroid-sensitive cases. In contrast, a neutrophil predominant noncanonical inflammation with regenerative epithelial cells and some indication of angiogenic endothelial response was overrepresented in areas from SR cases. Evaluation of potential prognostic biomarkers identified ubiquitin specific peptidase 17-like (USP17L) family of genes as being differentially expressed in immune cells from patients with worsened survival. In summary, we demonstrate distinct tissue niches with unique gene expression signatures within lower GI tissue from patients with aGVHD and provide evidence of a potential prognostic biomarker.
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Affiliation(s)
- Bidish K. Patel
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
| | - Michael J. Raabe
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
| | - Evan R. Lang
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
| | - Yuhui Song
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
| | - Chenyue Lu
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Linda T. Nieman
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
| | - Martin J. Aryee
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA
| | - Yi-Bin Chen
- Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA
| | - David T. Ting
- Center for Cancer Research, Mass General Cancer Center, Boston, MA
- Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Zachariah DeFilipp
- Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA
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9
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Lareau CA, Yin Y, Maurer K, Sandor KD, Daniel B, Yagnik G, Peña J, Crawford JC, Spanjaart AM, Gutierrez JC, Haradhvala NJ, Riberdy JM, Abay T, Stickels RR, Verboon JM, Liu V, Buquicchio FA, Wang F, Southard J, Song R, Li W, Shrestha A, Parida L, Getz G, Maus MV, Li S, Moore A, Roberts ZJ, Ludwig LS, Talleur AC, Thomas PG, Dehghani H, Pertel T, Kundaje A, Gottschalk S, Roth TL, Kersten MJ, Wu CJ, Majzner RG, Satpathy AT. Latent human herpesvirus 6 is reactivated in CAR T cells. Nature 2023; 623:608-615. [PMID: 37938768 PMCID: PMC10999258 DOI: 10.1038/s41586-023-06704-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/03/2023] [Indexed: 11/09/2023]
Abstract
Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.
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Affiliation(s)
- Caleb A Lareau
- Department of Pathology, Stanford University, Stanford, CA, USA.
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
- Department of Genetics, Stanford University, Stanford, CA, USA.
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Yajie Yin
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Katie Maurer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Katalin D Sandor
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Bence Daniel
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | | | - José Peña
- Allogene Therapeutics, South San Francisco, CA, USA
| | | | - Anne M Spanjaart
- Department of Hematology, University of Amsterdam, Amsterdam, the Netherlands
| | - Jacob C Gutierrez
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | | | - Janice M Riberdy
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Tsion Abay
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Robert R Stickels
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | | | - Vincent Liu
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Frank A Buquicchio
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Fangyi Wang
- Department of Pathology, Stanford University, Stanford, CA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Jackson Southard
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ren Song
- Allogene Therapeutics, South San Francisco, CA, USA
| | - Wenjing Li
- Allogene Therapeutics, South San Francisco, CA, USA
| | | | | | - Gad Getz
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Marcela V Maus
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Shuqiang Li
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Alison Moore
- Allogene Therapeutics, South San Francisco, CA, USA
| | | | - Leif S Ludwig
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Aimee C Talleur
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | | | | | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Theodore L Roth
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Marie J Kersten
- Department of Hematology, University of Amsterdam, Amsterdam, the Netherlands
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Robbie G Majzner
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
- Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Division of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Ansuman T Satpathy
- Department of Pathology, Stanford University, Stanford, CA, USA.
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
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10
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Khandelwal P, Lounder DT, Bartlett A, Haberman Y, Jegga AG, Ghandikota S, Koo J, Luebbering N, Leino D, Abdullah S, Loveless M, Minar P, Lake K, Litts B, Karns R, Nelson AS, Denson LA, Davies SM. Transcriptome analysis in acute gastrointestinal graft- versus host disease reveals a unique signature in children and shared biology with pediatric inflammatory bowel disease. Haematologica 2023; 108:1803-1816. [PMID: 36727399 PMCID: PMC10316272 DOI: 10.3324/haematol.2022.282035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion. Mitochondrial genes were among the top downregulated genes. Immune deconvolution identified a macrophage cellular signature. Weighted gene co-expression network analysis showed enrichment of genes in the ERK1/2 cascade. Transcriptome data from 206 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GvHD and UC. Comparison with the UC transcriptome showed both shared and distinct pathways. Both UC and GvHD transcriptomes shared an innate antimicrobial signature and FCγ1RA/CD64 was upregulated in both acute GvHD (log-fold increase 1.7, P=0.001) and UC. Upregulation of the ERK1/2 cascade pathway was specific to GvHD. We performed additional experiments to confirm transcriptomics. Firstly, we examined phosphorylation of ERK (pERK) by immunohistochemistry on GI biopsies (acute GvHD n=10, no GvHD n=10). pERK staining was increased in acute GvHD biopsies compared to biopsies without acute GvHD (P=0.001). Secondly, plasma CD64, measured by enzyme-linked immunsorbant assay (n=85) was elevated in acute GI GvHD (P<0.001) compared with those without and was elevated in GVHD compared with inflammatory bowel disease (n=47) (P<0.001), confirming the upregulated expression seen in the transcriptome.
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Affiliation(s)
- Pooja Khandelwal
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229.
| | - Dana T Lounder
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Allison Bartlett
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Yael Haberman
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Sheba Medical Center, Hashomer, affiliated with the Aviv University, Israel 52620
| | - Anil G Jegga
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Sudhir Ghandikota
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Jane Koo
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Nathan Luebbering
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Daniel Leino
- Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Sheyar Abdullah
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Michaela Loveless
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Phillip Minar
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Kelly Lake
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Bridget Litts
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Rebekah Karns
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Adam S Nelson
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Lee A Denson
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Stella M Davies
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
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11
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Flinn AM, Gennery AR. Recent advances in graft-versus-host disease. Fac Rev 2023; 12:4. [PMID: 36923700 PMCID: PMC10009889 DOI: 10.12703/r/12-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023] Open
Abstract
Acute and chronic graft-versus-host disease (GVHD) continue to present a significant challenge to physicians, accounting for considerable haematopoietic stem cell transplant (HSCT)-related morbidity and mortality, particularly those patients with steroid-refractory disease. In this review, we discuss recent advances in understanding the underlying pathophysiology, prevention and management of acute and chronic GVHD. Barriers to progress include the difficulty in obtaining high-quality evidence with sufficient patient numbers to identify optimal preventative and treatment strategies, with the heterogeneity of multiple patient, donor, graft and transplant-related factors, in addition to limited availability of human tissue to study the underlying pathophysiology, particularly in steroid-refractory disease. Continued collaborative efforts to improve our understanding of the pathophysiology involved, particularly in steroid-refractory disease, identification of biomarkers to permit risk stratification, and further well-designed randomised clinical trials are essential to help physicians determine optimal GVHD preventative and treatment strategies for each individual patient.
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Affiliation(s)
- Aisling M Flinn
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
- Great North Children’s Hospital, Newcastle upon Tyne, UK
| | - Andrew R Gennery
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
- Great North Children’s Hospital, Newcastle upon Tyne, UK
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12
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Wang J, Chang CY, Yang X, Zhou F, Liu J, Zhu S, Yu XZ, Liu C, O’Sullivan TE, Xie P, Feng Z, Hu W. Leukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity. Blood 2022; 140:2076-2090. [PMID: 35981499 PMCID: PMC9837439 DOI: 10.1182/blood.2022015677] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 07/29/2022] [Indexed: 01/21/2023] Open
Abstract
Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation, a widely used therapy for hematologic malignancies and blood disorders. Here, we report an unexpected role of cytokine leukemia inhibitory factor (LIF) in protecting against GVHD development. Administrating recombinant LIF protein (rLIF) protects mice from GVHD-induced tissue damage and lethality without compromising the graft-versus-leukemia activity, which is crucial to prevent tumor relapse. We found that rLIF decreases the infiltration and activation of donor immune cells and protects intestinal stem cells to ameliorate GVHD. Mechanistically, rLIF downregulates IL-12-p40 expression in recipient dendritic cells after irradiation through activating STAT1 signaling, which results in decreased major histocompatibility complex II levels on intestinal epithelial cells and decreased donor T-cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without compromising antileukemic efficacy.
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Affiliation(s)
- Jianming Wang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
| | - Chun-Yuan Chang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
| | - Xue Yang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
| | - Fan Zhou
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
| | - Juan Liu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
| | - Sining Zhu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Chen Liu
- Department of Pathology, Yale School of Medicine, New Haven, CT
| | - Timothy E. O’Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Department of Microbiology, Immunology & Molecular Genetics, Molecular Biology Institute, UCLA, Los Angeles, CA
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ
| | - Zhaohui Feng
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
| | - Wenwei Hu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
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13
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Lim JE, Sargur Madabushi S, Vishwasrao P, Song JY, Abdelhamid AMH, Ghimire H, Vanishree VL, Lamba JK, Dandapani S, Salhotra A, Lemecha M, Pierini A, Zhao D, Storme G, Holtan S, Aristei C, Schaue D, Al Malki M, Hui SK. Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice. Front Oncol 2022; 12:1045016. [PMID: 36439420 PMCID: PMC9686437 DOI: 10.3389/fonc.2022.1045016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022] Open
Abstract
Total body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limitations of TBI by delivering the prescribed dose targeted to the bone marrow (BM) while sparing organs at risk. Recently, our group demonstrated that TMI up to 20 Gy in relapsed/refractory AML patients was feasible and efficacious, significantly improving 2-year overall survival compared to the standard treatment. Whether such dose escalation is feasible in elderly patients, and how the organ toxicity profile changes when switching to TMI in patients of all ages are critical questions that need to be addressed. We used our recently developed 3D image-guided preclinical TMI model and evaluated the radiation damage and its repair in key dose-limiting organs in young (~8 weeks) and old (~90 weeks) mice undergoing congenic bone marrow transplant (BMT). Engraftment was similar in both TMI and TBI-treated young and old mice. Dose escalation using TMI (12 to 16 Gy in two fractions) was well tolerated in mice of both age groups (90% survival ~12 Weeks post-BMT). In contrast, TBI at the higher dose of 16 Gy was particularly lethal in younger mice (0% survival ~2 weeks post-BMT) while old mice showed much more tolerance (75% survival ~13 weeks post-BMT) suggesting higher radio-resistance in aged organs. Histopathology confirmed worse acute and chronic organ damage in mice treated with TBI than TMI. As the damage was alleviated, the repair processes were augmented in the TMI-treated mice over TBI as measured by average villus height and a reduced ratio of relative mRNA levels of amphiregulin/epidermal growth factor (areg/egf). These findings suggest that organ sparing using TMI does not limit donor engraftment but significantly reduces normal tissue damage and preserves repair capacity with the potential for dose escalation in elderly patients.
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Affiliation(s)
- Ji Eun Lim
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | | | - Paresh Vishwasrao
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Joo Y. Song
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Amr M. H. Abdelhamid
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
- Radiation Oncology Section, Department of Medicine and Surgery, Perugia University and General Hospital, Perugia, Italy
- Department of Oncology and Nuclear Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hemendra Ghimire
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - V. L. Vanishree
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Jatinder K. Lamba
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gianesville, FL, United States
| | - Savita Dandapani
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Amandeep Salhotra
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United States
| | - Mengistu Lemecha
- Department of Molecular and Cellular Biology, Beckman Research Institute, Duarte, CA, United States
| | - Antonio Pierini
- Division of Hematology and Bone Marrow Transplantation, Perugia General Hospital, Perugia, Italy
| | - Daohong Zhao
- Department of Biochemistry and Structural Biology, Univeristy of Texas (UT) Health San Antonio, San Antonio, TX, United States
| | - Guy Storme
- Department of Radiotherapy Universitair Ziekenhuis (UZ) Brussels, Brussels, Belgium
| | - Shernan Holtan
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Cynthia Aristei
- Radiation Oncology Section, Department of Medicine and Surgery, Perugia University and General Hospital, Perugia, Italy
| | - Dorthe Schaue
- Department of Radiation Oncology, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Monzr Al Malki
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United States
| | - Susanta K. Hui
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States
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14
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Copsel SN, Wolf D, Pfeiffer B, Barreras H, Perez VL, Levy RB. Recipient Tregs: Can They Be Exploited for Successful Hematopoietic Stem Cell Transplant Outcomes? Front Immunol 2022; 13:932527. [PMID: 35799783 PMCID: PMC9253768 DOI: 10.3389/fimmu.2022.932527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 05/18/2022] [Indexed: 02/03/2023] Open
Abstract
Human and mouse CD4+FoxP3+ T cells (Tregs) comprise non-redundant regulatory compartments which maintain self-tolerance and have been found to be of potential therapeutic usefulness in autoimmune disorders and transplants including allogeneic hematopoietic stem cell transplantation (allo-HSCT). There is substantial literature interrogating the application of donor derived Tregs for the prevention of graft versus host disease (GVHD). This Mini-Review will focus on the recipient's Tregs which persist post-transplant. Although treatment in patients with low dose IL-2 months post-HSCT are encouraging, manipulating Tregs in recipients early post-transplant is challenging, in part likely an indirect consequence of damage to the microenvironment required to support Treg expansion of which little is understood. This review will discuss the potential for manipulating recipient Tregs in vivo prior to and after HSCT (fusion proteins, mAbs). Strategies that would circumvent donor/recipient peripheral blood harvest, cell culture and ex-vivo Treg expansion will be considered for the translational application of Tregs to improve HSCT outcomes.
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Affiliation(s)
- Sabrina N. Copsel
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States
| | - Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, United States
| | - Brent Pfeiffer
- Department of Pediatrics, University of Miami School of Medicine, Miami, FL, United States
| | - Henry Barreras
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States
| | - Victor L. Perez
- Foster Center for Ocular Immunology, Duke Eye Center, Duke University, Durham, NC, United States
| | - Robert B. Levy
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States,Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, United States,Department of Ophthalmology, University of Miami School of Medicine, Miami, FL, United States,*Correspondence: Robert B. Levy,
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15
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Walton K, Walker K, Riddle M, Koehn BH, Reff J, Sagatys EM, Linden MA, Pidala J, Kim J, Lee MC, Kiluk JV, Hui JYC, Yun SY, Xing Y, Stefanski H, Lawrence HR, Lawrence NJ, Tolar J, Anasetti C, Blazar BR, Sebti SM, Betts BC. Dual JAK2/Aurora kinase A inhibition prevents human skin graft rejection by allo-inactivation and ILC2-mediated tissue repair. Am J Transplant 2022; 22:717-730. [PMID: 34668635 PMCID: PMC8897228 DOI: 10.1111/ajt.16870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 09/30/2021] [Accepted: 10/15/2021] [Indexed: 01/25/2023]
Abstract
Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. AJI-100 significantly reduces the frequency of skin-homing CLA+ donor T cells, limiting allograft invasion and tissue destruction by T effectors. AJI-100 also suppresses pathogenic Th1 and Th17 cells in the spleen yet spares beneficial regulatory T cells. We show dual JAK2/Aurora kinase A blockade enhances human type 2 innate lymphoid cell (ILC2) responses, which are capable of tissue repair. ILC2 differentiation mediated by GATA3 requires STAT5 phosphorylation (pSTAT5) but is opposed by STAT3. Further, we demonstrate that Aurora kinase A activation correlates with low pSTAT5 in ILC2s. Importantly, AJI-100 maintains pSTAT5 levels in ILC2s by blocking Aurora kinase A and reduces interference by STAT3. Therefore, combined JAK2/Aurora kinase A inhibition is an innovative strategy to merge immune suppression with tissue repair after transplantation.
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Affiliation(s)
- Kelly Walton
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Kirsti Walker
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Megan Riddle
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Brent H. Koehn
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Jordan Reff
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Elizabeth M. Sagatys
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA,Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA
| | - Michael A. Linden
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Joseph Pidala
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA,Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Blood and Marrow Transplantation – Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
| | - Jongphil Kim
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Marie C Lee
- Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - John V. Kiluk
- Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Sang Y. Yun
- Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA
| | - Yan Xing
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Heather Stefanski
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Harshani R. Lawrence
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA,Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA
| | - Nicholas J. Lawrence
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA,Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Claudio Anasetti
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA,Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Blood and Marrow Transplantation – Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
| | - Bruce R. Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Said M. Sebti
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia USA
| | - Brian C. Betts
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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16
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Schultz B, Miller DD, DeFor T, Blazar BR, Panoskaltsis‐Mortari A, Betts BC, MacMillan ML, Weisdorf DJ, Holtan SG. High Cutaneous Amphiregulin Expression Predicts Fatal Acute
Graft‐versus‐Host
Disease. J Cutan Pathol 2022; 49:532-535. [PMID: 35224759 PMCID: PMC9311189 DOI: 10.1111/cup.14218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 02/02/2022] [Accepted: 02/14/2022] [Indexed: 12/05/2022]
Abstract
Background Amphiregulin (AREG) is increased in circulation in acute graft‐versus‐host disease (aGVHD) and is associated with poor steroid response and lower survival. The expression of AREG in aGVHD target organs and its association with clinical outcomes are unknown. Methods We performed AREG immunohistochemical staining on skin specimens from 67 patients with aGVHD between the years 2010 and 2015. Two blinded reviewers assessed AREG expression and scored specimens with a semiquantitative scale ranging from 0 (absent) to 4 (most intense). Results Median AREG score of aGVHD cases was 3. Sixteen of 67 (23.9%) aGVHD cases had an AREG >3. High skin AREG expression (>3 vs. ≤3) was associated with increased overall clinical grade of aGVHD (52.9% vs. 33.4% clinical grade III‐IV, p = 0.02), reduced 3‐year overall survival (OS; 13% vs. 61%, p < 0.01), and increased 3‐year non‐relapse mortality (NRM; 56% vs. 20%, p = 0.05). Conclusion High skin AREG immunohistochemical expression is associated with high clinical grade aGVHD, poor OS, and increased NRM.
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Affiliation(s)
- Brittney Schultz
- Department of Dermatology University of Minnesota Minneapolis MN
| | - Daniel D. Miller
- Department of Dermatology University of Minnesota Minneapolis MN
| | - Todd DeFor
- Hematology and Transplant University of Minnesota Minneapolis MN
- Biostatistics and Informatics University of Minnesota Minneapolis MN
| | - Bruce R. Blazar
- Hematology and Transplant University of Minnesota Minneapolis MN
| | - Angela Panoskaltsis‐Mortari
- Hematology and Transplant University of Minnesota Minneapolis MN
- Department of Pediatrics University of Minnesota Minneapolis MN
| | - Brian C. Betts
- Hematology and Transplant University of Minnesota Minneapolis MN
| | - Margaret L. MacMillan
- Hematology and Transplant University of Minnesota Minneapolis MN
- Biostatistics and Informatics University of Minnesota Minneapolis MN
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17
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Song Q, Nasri U, Zeng D. Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model. Front Immunol 2022; 13:844271. [PMID: 35251043 PMCID: PMC8894323 DOI: 10.3389/fimmu.2022.844271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/26/2022] [Indexed: 11/23/2022] Open
Abstract
Intestinal graft-versus-host disease (Gut-GVHD) is one of the major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While systemic glucocorticoids (GCs) comprise the first-line treatment option, the response rate for GCs varies from 30% to 50%. The prognosis for patients with steroid-refractory acute Gut-GVHD (SR-Gut-aGVHD) remains dismal. The mechanisms underlying steroid resistance are unclear, and apart from ruxolitinib, there are no approved treatments for SR-Gut-aGVHD. In this review, we provide an overview of the current biological understanding of experimental SR-Gut-aGVHD pathogenesis, the advanced technology that can be applied to the human SR-Gut-aGVHD studies, and the potential novel therapeutic options for patients with SR-Gut-aGVHD.
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Affiliation(s)
- Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
- *Correspondence: Qingxiao Song,
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
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18
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Michniacki TF, Choi SW, Peltier DC. Immune Suppression in Allogeneic Hematopoietic Stem Cell Transplantation. Handb Exp Pharmacol 2022; 272:209-243. [PMID: 34628553 PMCID: PMC9055779 DOI: 10.1007/164_2021_544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for high-risk hematologic disorders. There are multiple immune-mediated complications following allo-HSCT that are prevented and/or treated by immunosuppressive agents. Principal among these immune-mediated complications is acute graft-versus-host disease (aGVHD), which occurs when the new donor immune system targets host tissue antigens. The immunobiology of aGVHD is complex and involves all aspects of the immune system. Due to the risk of aGVHD, immunosuppressive aGVHD prophylaxis is required for nearly all allogeneic HSCT recipients. Despite prophylaxis, aGVHD remains a major cause of nonrelapse mortality. Here, we discuss the clinical features of aGVHD, the immunobiology of aGVHD, the immunosuppressive therapies used to prevent and treat aGVHD, how to mitigate the side effects of these immunosuppressive therapies, and what additional immune-mediated post-allo-HSCT complications are also treated with immunosuppression.
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Affiliation(s)
- Thomas F Michniacki
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA
| | - Sung Won Choi
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Daniel C Peltier
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Hanaki R, Toyoda H, Iwamoto S, Morimoto M, Nakato D, Ito T, Niwa K, Amano K, Hashizume R, Tawara I, Hirayama M. Donor-derived M2 macrophages attenuate GVHD after allogeneic hematopoietic stem cell transplantation. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:1489-1499. [PMID: 34410039 PMCID: PMC8589365 DOI: 10.1002/iid3.503] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 12/28/2022]
Abstract
Introduction Graft‐versus‐host disease (GVHD) is frequent and fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT) and characteristically involves skin, gut, and liver. Macrophages promote tissue regeneration and mediate immunomodulation. Macrophages are divided into two different phenotypes, classically activated M1 (pro‐inflammatory or immune‐reactive macrophages) and alternatively activated M2 (anti‐inflammatory or immune‐suppressive macrophages). The anti‐inflammatory effect of M2 macrophage led us to test its effect in the pathophysiology of GVHD. Methods GVHD was induced in lethally irradiated BALB/c mice. M2 macrophages derived from donor bone marrow (BM) were administered intravenously, while controls received donor BM‐mononuclear cells and splenocytes. Animals were monitored for clinical GVHD and analyzed. Results We confirmed that administering donor BM‐derived M2 macrophages attenuated GVHD severity and prolonged survival after HSCT. Moreover, donor BM‐derived M2 macrophages significantly suppressed donor T cell proliferation by cell‐to‐cell contact in vitro. Conclusions We showed the protective effects of donor‐derived M2 macrophages on GVHD and improved survival in a model of HSCT. Our data suggest that donor‐derived M2 macrophages offer the potential for cell‐based therapy to treat GVHD.
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Affiliation(s)
- Ryo Hanaki
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hidemi Toyoda
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shotaro Iwamoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Mari Morimoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Daisuke Nakato
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Takahiro Ito
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kaori Niwa
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Keishiro Amano
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Ryotaro Hashizume
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Isao Tawara
- Department of Hematology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Masahiro Hirayama
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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Yang J, Wang C, Huang K, Zhang M, Wang J, Pan X. Compound Lactobacillus sp. administration ameliorates stress and body growth through gut microbiota optimization on weaning piglets. Appl Microbiol Biotechnol 2020; 104:6749-6765. [PMID: 32556411 DOI: 10.1007/s00253-020-10727-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 05/24/2020] [Accepted: 06/07/2020] [Indexed: 02/07/2023]
Abstract
The composition of bacteria in the gastrointestinal tract of piglets is easily affected by environmental changes, particularly during the weaning period. Compound strains of Lactobacillus reuteri and Lactobacillus salivarius were supplemented to piglets during pre- and post-weaning to determine their effects in improving the growth performance and ameliorating the diarrhea rate and stress caused by antioxidation in piglets. A larger number of L. reuteri and L. salivarius colonized the distal segment of the ileum and the total numbers of Lactobacillus spp. and Bifidobacteria were higher in the ileal mucous membrane and cecal lumen with probiotics supplementation. The numbers of antioxidants and immune molecules increased, levels of cortisol and endotoxin reduced, and growth hormone and insulin-like growth factor 1 improved in the plasma following compound bacteria (CL) supplementation. Spearman's and KEGG analysis of the bacterial operational taxonomic unit and antioxidative and immune indices and metabolic genes indicated that the body growth modulation by CL supplementation could be attributed to optimization of the intestinal bacterial composition; functional strains of L. delbrueckii, L. salivarius, L. formicilis, L. reuteri, and L. mucosae were positively correlated with body antioxidation and immunity derived by CL supplementation. Strains of L. agilis and L. pontis were diverse and negatively correlated with body antioxidation and immunity. Collectively, these results suggest that supplementation with CL could reduce stress and improve the growth performance of piglets during weaning by optimizing the intestinal bacterial composition. KEY POINTS: • The colonization of L. reuteri and L. salivarius in ileal mucous membrane optimize bacterial composition of GIT, mainly some functional strains of Lactobacillus, L. delbrueckii, L. salivarius, L. formicilis, L. reuteri, and L. mucosae. • The optimized bacterial composition of piglets in both ileal mucous membrane and cecal content improves body growth hormone level, immunity, and antioxidation, which is helpful to defend the stress. These benefits induce to increased growth performance of animal model piglets during weaning.
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Affiliation(s)
- Jiajun Yang
- Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agriculture Science, Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, No. 40 of NongKe South of Road, Hefei, 230031, Anhui, China
| | - Chonglong Wang
- Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agriculture Science, Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, No. 40 of NongKe South of Road, Hefei, 230031, Anhui, China. .,Key Laboratory of Pig Molecular Quantitative Genetics, Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agricultural Sciences, No. 40 of Nongke South Road, Hefei, 230031, Anhui, China.
| | - Kehe Huang
- Institute of Nutritional and Metabolic Disorders, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Minhong Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Yuanminyuan West Road, Haidian District, Beijing, 100094, China
| | - Jing Wang
- Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agriculture Science, Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, No. 40 of NongKe South of Road, Hefei, 230031, Anhui, China.,Key Laboratory of Pig Molecular Quantitative Genetics, Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agricultural Sciences, No. 40 of Nongke South Road, Hefei, 230031, Anhui, China
| | - Xiaocheng Pan
- Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agriculture Science, Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, No. 40 of NongKe South of Road, Hefei, 230031, Anhui, China.,Livestock and Poultry Epidemic Diseases Research Center of Anhui Province, Hefei, 230031, Anhui, China
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21
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Hong YQ, Wan B, Li XF. Macrophage regulation of graft- vs-host disease. World J Clin Cases 2020; 8:1793-1805. [PMID: 32518770 PMCID: PMC7262718 DOI: 10.12998/wjcc.v8.i10.1793] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 02/05/2023] Open
Abstract
Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells’ reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.
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Affiliation(s)
- Ya-Qun Hong
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
| | - Bo Wan
- Faculty of Life Sciences and Medicine, King’s College London, London WC1N 3BG, United Kingdom
| | - Xiao-Fan Li
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
- INSERM U1160, Hospital Saint Louis, Université Paris Diderot, Paris 94430, France
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